CFRD is associated with worse nutritional status, greater pulmonary function decline, and increased mortality. CFRD arises primarily from compromised insulin secretion--traditionally considered a by- product of pancreatic exocrine tissue damage and fibrosis. Recent developments in the field of type 2 diabetes (T2D) are propelling a re-examination of this basic explanation. For example, islet cell amyloid, a feature of T2D and a marker of endoplasmic reticulum stress, is found in pancreatic islets in CF. Genome-wide association studies have associated genetic variants in TCF7L2, a transcription factor implicated in enteroendocrine function, with increased susceptibility to T2D and CFRD. Decreased secretion of GLP-1 and decreased responsiveness of insulin secretion to GIP, both incretins, have been identified in T2D, but have received minimal attention in CFRD. Moreover, the mechanisms underlying CFRD development have been minimally explored. We hypothesize that 1) acute incretin exposure and chronic incretin-based therapy will improve -cell sensitivity to glucose in patients with early glucose abnormalities and in patients with CFRD, 2) incretin-based therapy with sitagliptin (a T2D therapy that inhibits breakdown of incretins) will improve insulin secretion and glucose excursion during a mixed meal, and 3) insulin secretory capacity, -cell sensitivity to glucose, and incretin secretion are decreased in non-diabetic CF subjects homozygous for the T2D-risk conferring TCF7L2 allele vs the wildtype TCF7L2 allele. We propose cross sectional and 6-month intervention studies to test these hypotheses. Forty-five CF adolescents and adults with Indeterminate glucose tolerance, impaired glucose tolerance, and CFRD will undergo Glucose Potentiated Arginine Tests (GPA, which measures -cell secretory capacity and sensitivity to glucose); these will be performed in the presence and absence of acute incretin (GIP or GLP-1) exposure. The impact of six months of incretin-based therapy (sitagliptin) upon glucose excursion and incretin and insulin secretion during the Mixed Meal Tolerance Test, and -cell secretory capacity and sensitivity to glucose during the GPA will be tested. Similar studies will be completed in thirty non-diabetic children and adults homozygous for the T2D-risk conferring TCF7L2 allele vs the wildtype TCF7L2 allele. We anticipate that in CF disturbed incretin secretion contributes to impaired insulin secretion, that incretin-based therapy can improve insulin secretion, and that the T2D-conferring genotype is associated with aberrant incretin regulated insulin secretion. Such sophisticated phenotyping of insulin and incretin secretion has not previously been undertaken. The knowledge gained will better define the mechanisms responsible for insulin secretion defects in CF, identify potential interventions to interrupt progressive insulin deficiency, and may uncover early insulin secretion disturbances that will predict not only progression to CFRD but concurrent risk of worsening pulmonary status. PUBLIC HEALTH RELEVANCE: The mechanisms underlying development of cystic fibrosis related diabetes (CFRD), a common co-morbidity in cystic fibrosis (CF) associated with increased morbidity and mortality, are poorly understood. This study will explore the role of incretins (hormones secreted by the intestine that can modulate insulin secretion), defects in -cell sensitivity to glucose, and genetics in CFRD. This evidence may serve as the platform upon which to develop new treatment modalities aimed at preserving -cell function.